Kappa opioid ligands

ABSTRACT

The invention provides novel ligands of Kappa (κ) opioid receptors, such as can be used to modulate a Kappa opioid receptor. Methods of synthesis and methods of use are also provided. Compounds of the invention can be used therapeutically in the treatment of dissociative disorders or pain, or to provide neuroprotection, or to induce diuresis, or to modulate the immune system, or for treatment of one or more of an affective disorders comprising depression or stress/anxiety; an addictive disorder; alcoholism, epilepsy; a cognition deficiency; schizophrenia; Alzheimer&#39;s disease; or pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. national stage application filed under 35U.S.C. §371 from International Application Serial No. PCT/US2013/055313,which was filed Aug. 16, 2013, and published as WO 2014/028829 on Feb.20, 2014, and which claims the priority of U.S. provisional applicationSer. No. 61/683,861, filed Aug. 16, 2012, which applications andpublication are incorporated by reference as if reproduced herein andmade a part hereof in their entirety, and the benefit of priority ofeach of which is claimed herein.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under grant numberMH084512-02, awarded by the National Institutes of Health. The U.S.government has certain rights in the invention.

BACKGROUND

The kappa-opioid receptor (KOR) is a member of the opioid receptorfamily which binds the opioid peptide dynorphin as the primaryendogenous ligand. KOR has a wide, yet distinct distribution in thebrain, spinal cord, and in pain neurons. Recently, there have beensignificant advances in understanding the role of KOR in controllingcognition and emotion in addition to insights into its involvement inneurological diseases such as epilepsy and neuropathic pain. Thesepathologies share the common feature of disruption of the induction ofneuroplasticity. While this is not a particularly novel idea inepilepsy, an emerging scheme in the field of psychiatric disorders isthat diseases such as addition and depression also stem from disruptionin normal synaptic physiology and aberrant neuroplasticity thatultimately lead to maladaptive learning. Kappa opioid receptors haverecently been investigated for their therapeutic potential in thetreatment of addiction (Hasebe K, Kawai K, Suzuki T, Kawamura K, TanakaT, Narita M, Nagase H, Suzuki T (2004) “Possible pharmacotherapy of theopioid kappa receptor agonist for drug dependence” Annals of the NewYork Academy of Sciences 1025: 404-13), and evidence points towardsdynorphin to be one of the body's natural addiction control mechanism(Frankel P S, Alburges M E, Bush L, Hanson G R, Kish S J (2008)“Striatal and ventral pallidum dynorphin concentrations are markedlyincreased in human chronic cocaine users” Neuropharmacology 55 (1):41-6).

In experimental “addiction” models the kappa-opioid receptor has alsobeen shown to influence stress-induced relapse to drug seeking behavior.For the drug dependent individual, risk of relapse is a major obstacleto becoming drug free. Recent reports demonstrated that KOR are requiredfor stress-induced reinstatement of cocaine seeking (Beardsley P M,Howard J L, Shelton K L, Carroll F I (2005) “Differential effects of thenovel kappa opioid receptor antagonist, JDTic, on reinstatement ofcocaine-seeking induced by footshock stressors vs cocaine primes and itsantidepressant-like effects in rats” Psychopharmacology (Berl.) 183 (1):118-26; Redila V A, Chavkin C (2008). “Stress-induced reinstatement ofcocaine seeking is mediated by the kappa opioid system”Psychopharmacology 200 (1): 59-70; Blum K, Braverman E R, Holder J M,Lubar J F, Monastra V J, Miller D, Lubar J O, Chen T J, Comings D E(2000) “Reward deficiency syndrome: a biogenetic model for the diagnosisand treatment of impulsive, addictive, and compulsive behaviors” Journalofpsychoactive drugs 32 Suppl: i-iv, 1-112). It has also been reportedthat the dynorphin-Kappa opioid system is critical for stress-induceddrug seeking. In animal models, stress has been demonstrated topotentiate cocaine reward behavior in a kappa opioid-dependent manner(McLaughlin J P, Marton-Popovici M, Chavkin C. (2003) “Kappa opioidreceptor antagonism and prodynophin gene disruption block stress-inducedbehavioral responses” The Journal of Neuroscience 23 (13): 5674-83;Mash, Deborah C. (2006) “Social defeat stress-induced behavioralresponses are mediated by the endogenous kappa opioid system”Neuropsychopharmacology 31 (4): 787-94). These effects are likely causedby stress-induced drug craving that requires activation of thedynorphin-KOR system. Although seemingly paradoxical, it is well knownthat drug taking results in a change from homeostasis to allostasis.

It has been suggested that withdrawal-induced dysphoria orstress-induced dysphoria may act as a driving force by which theindividual seeks alleviation via drug taking. The rewarding propertiesof the drug are altered, and it is clear kappa-opioid activationfollowing stress increase its rewarding properties and causepotentiation of reward behavior, or reinstatement to drug seeking. Thestress-induced activation of kappa-opioid receptors is likely due tomultiple signaling mechanisms. The kappa-opioid receptors have markedeffects on all types of addiction including alcohol and opiate abuse.Cocaine addiction, as well as addiction to alcohol or other drug, is aworld wide problem that has serious social, mental, and physicalconsequences. While various forms of prevention and/or treatment ofaddiction have been attempted, there remains a need for an improvement.For example, small molecules have been used as drugs to decrease thephysical and/or mental conditions associated with addiction.

It is now thought that dysphoric elements of stress contributed to thedevelopment of anxiety states and clinical depression. There is recentevidence to suggest that dysphoric components of stress are encoded bythe dynorphin-KOR system (Land B B, Bruchas M R, Lemos J C, Xu M, MeliefE J, Chavkin C (2008) “The dysphoric component of stress is encoded byactivation of the dynorphin kappa-opioid system” J Neurosci28(2):407-414). It has been demonstrated that stress decreases BDNFexpression, which in turn predisposes the individual to depressive mood.Acute pretreatment with high doses of norBNI has been shown to increaseBDNF mRNA expression in the area of hippocampus and the amygdala (ZhangH, Shi Y G, Woods J H, Watson S J, Ko M C (2007) “Central kappa-opioidreceptor mediated antidepressant-like effects of nor Binaltorphimine:behavioral and BDNF mRNA expression studies” Eur J Pharmacol570(1-3):89-96; Duman R S, Monteggia L M (2006) “A neurotrophic modelfor stress-related mood disorders” Biol Psychiatry 59(12):1116-1127).

Several behavioral studies using KOR agonists/antagonists as well asknockout animals have demonstrated a potential role for thedynorphin-KOR system in analgesia of neuropathic pain. (Gaveriaux-RuffC, Kieffer B L (2002) “Opioid receptor genes inactivated in mice: thehighlights” Neuropeptides 36 (2-3): 62-71).

There is a body of evidence to suggest that dynorphin peptide andmessage expression is up-regulated in both epileptic humans and animalmodels of epilepsy, suggesting that the dynorphin-KOR system play asignificant role in the disease. (Bausch S B, Esteb T M, Terman G W,Chavkin C (1998) “Administered and endogenously released kappa opioidsdecrease pilocarpine-induced seizures and seizure-inducedhistopathology” J Pharmacol Exp Ther 284(3): 1147-1155; de Lanerolle NC, Williamson A, Meredith C et al (1997) “Dynorphin and the kappa 1ligand [3H] U69,593 binding in the human epileptogenic hippocampus”Epilepsy Res 28(3): 189-205; Loacker S, Sayyah M, Wittmann W, Herzog H,Schwarzer C (2007) “Endogenous dynorphin in epileptogenesis andepilepsy: anticonvulsant net effect via kappa opioid receptors” Brain130(pt 4): 1017-1028; Houser C R, Miyashiro J E, Swartz B E, Walsh G O,Rich J R, Delgado-Escueta A V (1990) “Altered patterns of dynorphinimmunoreactivity suggest mossy fiber reorganization in human hippocampalepilepsy” J Neurosci 10(1):267-282; De Sarro G B, De Sarro A (1993)“Anticonvulsant properties of non-competitive antagonists of theN-methyl-D-aspartate receptor in genetically epilepsy-prone rats:comparison with CPPene” Neuropharmacology 32(1):51-58).

It has been suggested that the dynorphin-KOR system is involved in thelearning process. A negative correlation between the level of spatiallearning and the level of dinorphin immunoreactivity in the hippocampalformation has been demonstrated (Jiang H K, Owyang V V, Hong J S,Gallagher M (1989) “Elevated dynorphin in the hippocampal formation ofaged rats: relation to cognitive impairment on a spatial learning task”Proc Natl Acad Sci USA 86(8):2948-2951). In humans, the brain ofAlzheimer disease patients have significant increase in dynorphinexpression compared to age matched controls (Mathieu-Kia A M, Fan L Q,Kreek M J, Simon E J, Hiller J M (2001) “Mu-, delta- and kappa-opioidreceptor populations are differentially altered in distinct areas ofpostmortem brains of Alzheimer's disease patients” Brain Res 893(1-2):121-134).

SUMMARY

The present invention is directed in various embodiments to novelligands of kappa opioid receptors, i.e., modulators of the class ofopioid receptors termed Kappa (κ) receptors. In various embodiments, theinvention provides a compound of formula (I)

wherein

the ring designated A can further comprise an additional nitrogen atomin any position that bears any of W, X, Y, or Z, provided that therespective group W, X, Y, or Z is absent from that position;

W is H, (C1-C6)alkyl, (C1-C6)haloalkyl, hydroxy(C1-C6)alkyl,(C3-C9)cycloalkyl, or halo;

X is H, halo, nitro, (C1-C6)alkyl, (C1-C6)haloalkyl,hydroxy(C1-C6)alkyl, (C3-C9)cycloalkyl, NR^(a)R^(b),N(R^(a))C(═O)(C1-C6)alkyl, CO₂R, or heteroaryl;

Y is H, halo, (C1-C6)alkyl, (C3-C9)cycloalkyl, or halo;

Z is halo, hydroxy, CO₂R, C(═O)NR₂, CN, heteroaryl(C₀-C₆)alkyl,hydroxy(C1-C6)alkyl, HC(═O), HC(═O), (C1-C6)C(═O), or CR(═NOR);

wherein each independently selected R is H, (C1-C6)alkyl,(C3-C9)cycloalkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C6)alkyl;

or, any adjacent pair of W, X, and Y, can together with the atoms towhich they are bonded form a fused cycloalkyl, heterocyclyl, or aryl, orheteroaryl, any of which can be mono- or independently multi-substitutedwith (C1-C6)alkyl, (C3-C9)cycloalkyl, halo, nitro, NR^(a)R^(b),N(R^(a))C(═O)(C1-C6)alkyl, CO₂R, or heteroaryl;

wherein any alkyl, cycloalkyl, aryl, or heteroaryl of W, X, Y, or Z, canbe unsubstituted or can be mono- or independently multi-substituted with(C1-C6)alkyl, (C3-C9)cycloalkyl, halo, nitro, NR^(a)R^(b),N(R^(a))C(═O)(C1-C6)alkyl, CO₂R, or heteroaryl;

the ring system Cyc, comprising the nitrogen atom, comprises a mono-,bi-, or tri-cyclic heterocyclyl bonded to ring A via the nitrogen atom,wherein Cyc comprises a 4, 5, 6, 7, or 8 membered ring, optionallybridged with one or two bridges independently comprising 0, 1, or 2carbon atoms, the ring system Cyc optionally containing 1 or 2additional heteroatoms selected from NR, O, or S(O)_(q) wherein q=0, 1,or 2; wherein R¹, and optionally, m independently selected R², arebonded to the ring system Cyc, m=0, 1, or 2;

R¹ is (CH₂)_(n)NR^(a)R^(b), wherein R^(a) and R^(b) are eachindependently H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, orheterocyclylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, or heterocyclylalkyl, is substituted with 0, 1, 2, 3, or 4independently selected J, and wherein any heterocyclyl or cycloalkyl ismono-, bi-, or tri-cyclic; or R^(a) and R^(b) together with the nitrogenatom to which they are bonded form a heterocyclyl ring substituted with0, 1, 2, 3, or 4 independently selected J, wherein n=0, 1, or 2;

or R¹ is (CH₂)_(p1)NR^(a)(CH₂)_(p2) bonded to two carbon atoms of Cyc toform a 5-, 6-, or 7-membered heterocyclyl substituted with 0, 1, 2, 3,or 4 independently selected J, p1 and p2 are independently 0, 1, or 2,provided that p1+p2 is no less than 2;

R² is (C1-C6)alkyl, hydroxy(C1-C6)alkyl, OR, CO₂R, or halo, wherein m=0,1, or 2;

J is independently at each occurrence OR, (C1-C6)alkyl,hydroxy(C1-C6)alkyl, (C3-C9)cycloalkyl, CO₂R, or halo;

or any pharmaceutically acceptable salt thereof.

In various embodiments, the invention provides a pharmaceuticalcomposition, comprising a compound of the invention and apharmaceutically acceptable excipient.

In various embodiments, the invention provides a method of modulating aKappa opioid receptor, comprising contacting the receptor with aneffective amount or concentration of a compound of formula (I) of theinvention. The Kappa opioid receptor can be disposed within living humantissue, such as in a patient suffering from a dissociative disorder, orfrom pain.

In various embodiments, the invention provides a method of treatment ofa dissociative disorder or pain in a patient in need thereof, comprisingadministering to the patient an effective amount or concentration of acompound of formula (I) of the invention at a frequency and for aduration to provide a beneficial effect to the patient.

In various embodiments, the invention provides a method of providingneuroprotection to a patient comprising administering to the patient aneffective amount or concentration of a compound of formula (I) of theinvention at a frequency and for a duration to provide a beneficialeffect to the patient.

In various embodiments, the invention provides a method of modulatingthe immune system in a patient, comprising administering to the patientan effective amount or concentration of a compound of formula (I) of theinvention at a frequency and for a duration to provide a beneficialeffect to the patient.

In various embodiments, the invention provides a method of inducingdiuresis in a patient, comprising administering to the patient aneffective amount or concentration of a compound of formula (I) of theinvention at a frequency and for a duration to provide a beneficialeffect to the patient.

DETAILED DESCRIPTION Definitions

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise.

The term “about” as used herein, when referring to a numerical value orrange, allows for a degree of variability in the value or range, forexample, within 10%, or within 5% of a stated value or of a stated limitof a range.

All percent compositions are given as weight-percentages, unlessotherwise stated.

All average molecular weights of polymers are weight-average molecularweights, unless otherwise specified.

As used herein, “individual” (as in the subject of the treatment) or“patient” means both mammals and non-mammals. Mammals include, forexample, humans; non-human primates, e.g. apes and monkeys; andnon-primates, e.g. dogs, cats, cattle, horses, sheep, and goats.Non-mammals include, for example, fish and birds.

The term “disease” or “disorder” or “malcondition” are usedinterchangeably, and are used to refer to diseases or conditions whereina kappa (κ) opioid receptor plays a role in the biochemical mechanismsinvolved in the disease or malcondition or symptom(s) thereof such thata therapeutically beneficial effect can be achieved by acting on a kappaopioid receptor. “Acting on” a kappa opioid receptor, or “modulating” akappa opioid receptor, can include binding to a kappa opioid receptorand/or inhibiting the bioactivity of a kappa opioid receptor and/orallosterically regulating the bioactivity of a kappa opioid receptor invivo.

The expression “effective amount”, when used to describe therapy to anindividual suffering from a disorder, refers to the amount of a compoundof the invention that is effective to inhibit or otherwise act on akappa opioid receptor in the individual's tissues wherein a kappa opioidreceptor involved in the disorder is active, wherein such inhibition orother action occurs to an extent sufficient to produce a beneficialtherapeutic effect.

“Substantially” as the term is used herein means completely or almostcompletely; for example, a composition that is “substantially free” of acomponent either has none of the component or contains such a traceamount that any relevant functional property of the composition isunaffected by the presence of the trace amount, or a compound is“substantially pure” is there are only negligible traces of impuritiespresent.

“Treating” or “treatment” within the meaning herein refers to analleviation of symptoms associated with a disorder or disease, orinhibition of further progression or worsening of those symptoms, orprevention or prophylaxis of the disease or disorder, or curing thedisease or disorder. Similarly, as used herein, an “effective amount” ora “therapeutically effective amount” of a compound of the inventionrefers to an amount of the compound that alleviates, in whole or inpart, symptoms associated with the disorder or condition, or halts orslows further progression or worsening of those symptoms, or prevents orprovides prophylaxis for the disorder or condition. In particular, a“therapeutically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredtherapeutic result.

A therapeutically effective amount is also one in which any toxic ordetrimental effects of compounds of the invention are outweighed by thetherapeutically beneficial effects.

Phrases such as “under conditions suitable to provide” or “underconditions sufficient to yield” or the like, in the context of methodsof synthesis, as used herein refers to reaction conditions, such astime, temperature, solvent, reactant concentrations, and the like, thatare within ordinary skill for an experimenter to vary, that provide auseful quantity or yield of a reaction product. It is not necessary thatthe desired reaction product be the only reaction product or that thestarting materials be entirely consumed, provided the desired reactionproduct can be isolated or otherwise further used.

By “chemically feasible” is meant a bonding arrangement or a compoundwhere the generally understood rules of organic structure are notviolated; for example a structure within a definition of a claim thatwould contain in certain situations a pentavalent carbon atom that wouldnot exist in nature would be understood to not be within the claim. Thestructures disclosed herein, in all of their embodiments are intended toinclude only “chemically feasible” structures, and any recitedstructures that are not chemically feasible, for example in a structureshown with variable atoms or groups, are not intended to be disclosed orclaimed herein.

An “analog” of a chemical structure, as the term is used herein, refersto a chemical structure that preserves substantial similarity with theparent structure, although it may not be readily derived syntheticallyfrom the parent structure. A related chemical structure that is readilyderived synthetically from a parent chemical structure is referred to asa “derivative.”

When a substituent is specified to be an atom or atoms of specifiedidentity, “or a bond”, a configuration is referred to when thesubstituent is “a bond” that the groups that are immediately adjacent tothe specified substituent are directly connected to each other in achemically feasible bonding configuration.

All chiral, diastereomeric, racemic forms of a structure are intended,unless a particular stereochemistry or isomeric form is specificallyindicated. Compounds used in the present invention can include enrichedor resolved optical isomers at any or all asymmetric atoms as areapparent from the depictions, at any degree of enrichment. Both racemicand diastereomeric mixtures, as well as the individual optical isomerscan be isolated or synthesized so as to be substantially free of theirenantiomeric or diastereomeric partners, and these are all within thescope of the invention.

As used herein, the terms “stable compound” and “stable structure” aremeant to indicate a compound that is sufficiently robust to surviveisolation to a useful degree of purity from a reaction mixture, andformulation into an efficacious therapeutic agent. Only stable compoundsare contemplated herein.

A “small molecule” refers to an organic compound, including anorganometallic compound, of a molecular weight less than about 2 kDa,that is not a polynucleotide, a polypeptide, a polysaccharide, or asynthetic polymer composed of a plurality of repeating units.

As to any of the groups described herein, which contain one or moresubstituents, it is understood that such groups do not contain anysubstitution or substitution patterns which are sterically impracticaland/or synthetically non-feasible. In addition, the compounds of thisdisclosed subject matter include all stereochemical isomers arising fromthe substitution of these compounds.

In various embodiments, the compound or set of compounds, such as areamong the inventive compounds or are used in the inventive methods, canbe any one of any of the combinations and/or sub-combinations of theabove-listed embodiments.

When a group, e.g., an “alkyl” group, is referred to without anylimitation on the number of atoms in the group, it is understood thatthe claim is definite and limited with respect the size of the alkylgroup, both by definition; i.e., the size (the number of carbon atoms)possessed by a group such as an alkyl group is a finite number, lessthan the total number of carbon atoms in the universe and bounded by theunderstanding of the person of ordinary skill as to the size of thegroup as being reasonable for a molecular entity; and by functionality,i.e., the size of the group such as the alkyl group is bounded by thefunctional properties the group bestows on a molecule containing thegroup such as solubility in aqueous or organic liquid media. Therefore,a claim reciting an “alkyl” or other chemical group or moiety isdefinite and bounded, as the number of atoms in the group cannot beinfinite.

The inclusion of an isotopic form of one or more atoms in a moleculethat is different from the naturally occurring isotopic distribution ofthe atom in nature is referred to as an “isotopically labeled form” ofthe molecule. All isotopic forms of atoms are included as options in thecomposition of any molecule, unless a specific isotopic form of an atomis indicated. For example, any hydrogen atom or set thereof in amolecule can be any of the isotopic forms of hydrogen, i.e., protium(¹H), deuterium (²H), or tritium (³H) in any combination. Similarly, anycarbon atom or set thereof in a molecule can be any of the isotopic formof carbons, such as ¹¹C, ¹²C, ¹³C, or ¹⁴C, or any nitrogen atom or setthereof in a molecule can be any of the isotopic forms of nitrogen, suchas ¹³N, ¹⁴N, or ¹⁵N. A molecule can include any combination of isotopicforms in the component atoms making up the molecule, the isotopic formof every atom forming the molecule being independently selected. In amulti-molecular sample of a compound, not every individual moleculenecessarily has the same isotopic composition. For example, a sample ofa compound can include molecules containing various different isotopiccompositions, such as in a tritium or ¹⁴C radiolabeled sample where onlysome fraction of the set of molecules making up the macroscopic samplecontains a radioactive atom. It is also understood that many elementsthat are not artificially isotopically enriched themselves are mixturesof naturally occurring isotopic forms, such as ¹⁴N and ¹⁵N, ³²S and ³⁴S,and so forth. A molecule as recited herein is defined as includingisotopic forms of all its constituent elements at each position in themolecule. As is well known in the art, isotopically labeled compoundscan be prepared by the usual methods of chemical synthesis, exceptsubstituting an isotopically labeled precursor molecule. The isotopes,radiolabeled or stable, can be obtained by any method known in the art,such as generation by neutron absorption of a precursor nuclide in anuclear reactor, by cyclotron reactions, or by isotopic separation suchas by mass spectrometry. The isotopic forms are incorporated intoprecursors as required for use in any particular synthetic route. Forexample, ¹⁴C and ³H can be prepared using neutrons generated in anuclear reactor. Following nuclear transformation, ¹⁴C and ³H areincorporated into precursor molecules, followed by further elaborationas needed.

The term “amino protecting group” or “N-protected” as used herein refersto those groups intended to protect an amino group against undesirablereactions during synthetic procedures and which can later be removed toreveal the amine. Commonly used amino protecting groups are disclosed inProtective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M.,John Wiley & Sons, New York, N.Y., (3rd Edition, 1999). Amino protectinggroups include acyl groups such as formyl, acetyl, propionyl, pivaloyl,t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl,trichloroacetyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl,4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonylgroups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy-or aryloxy-carbonyl groups (which form urethanes with the protectedamine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl,isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl(Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyland the like; and silyl groups such as trimethylsilyl and the like.Amine protecting groups also include cyclic amino protecting groups suchas phthaloyl and dithiosuccinimidyl, which incorporate the aminonitrogen into a heterocycle. Typically, amino protecting groups includeformyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc,Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of theordinary artisan to select and use the appropriate amino protectinggroup for the synthetic task at hand.

The term “hydroxyl protecting group” or “O-protected” as used hereinrefers to those groups intended to protect an OH group againstundesirable reactions during synthetic procedures and which can later beremoved to reveal the amine. Commonly used hydroxyl protecting groupsare disclosed in Protective Groups in Organic Synthesis, Greene, T. W.;Wuts, P. G. M., John Wiley & Sons, New York, N.Y., (3rd Edition, 1999).Hydroxyl protecting groups include acyl groups such as formyl, acetyl,propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl,trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, α-chlorobutyryl,benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like;sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like;acyloxy groups (which form urethanes with the protected amine) such asbenzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl,isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl(Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyland the like; and silyl groups such as trimethylsilyl and the like. Itis well within the skill of the ordinary artisan to select and use theappropriate hydroxyl protecting group for the synthetic task at hand.

In general, “substituted” refers to an organic group as defined hereinin which one or more bonds to a hydrogen atom contained therein arereplaced by one or more bonds to a non-hydrogen atom such as, but notlimited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groupssuch as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxygroups, oxo(carbonyl) groups, carboxyl groups including carboxylicacids, carboxylates, and carboxylate esters; a sulfur atom in groupssuch as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups,sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atomin groups such as amines, hydroxylamines, nitriles, nitro groups,N-oxides, hydrazides, azides, and enamines; and other heteroatoms invarious other groups. Non-limiting examples of substituents J that canbe bonded to a substituted carbon (or other) atom include F, Cl, Br, I,OR′, OC(O)N(R′)₂, CN, NO, NO₂, ONO₂, azido, CF₃, OCF₃, R′, O (oxo), S(thiono), methylenedioxy, ethylenedioxy, N(R′)₂, SR′, SOR′, SO₂R′,SO₂N(R′)₂, SO₃R′, C(O)R′, C(O)C(O)R′, C(O)CH₂C(O)R′, C(S)R′, C(O)OR′,OC(O)R′, C(O)N(R′)₂, OC(O)N(R′)₂, C(S)N(R′)₂, (CH₂)₀₋₂N(R′)C(O)R′,(CH₂)₀₋₂N(R′)N(R′)₂, N(R′)N(R′)C(O)R′, N(R′)N(R′)C(O)OR′,N(R′)N(R′)CON(R′)₂, N(R′)SO₂R′, N(R′)SO₂N(R′)₂, N(R′)C(O)OR′,N(R′)C(O)R′, N(R′)C(S)R′, N(R′)C(O)N(R′)₂, N(R′)C(S)N(R′)₂, N(COR′)COR′,N(OR′)R′, C(═NH)N(R′)₂, C(O)N(OR′)R′, or C(═NOR′)R′ wherein R′ can behydrogen or a carbon-based moiety, and wherein the carbon-based moietycan itself be further substituted; for example, wherein R′ can behydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heteroaryl, or heteroarylalkyl, wherein any alkyl, acyl, cycloalkyl,aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl or R′ can beindependently mono- or multi-substituted with J; or wherein two R′groups bonded to a nitrogen atom or to adjacent nitrogen atoms cantogether with the nitrogen atom or atoms form a heterocyclyl, which canbe mono- or independently multi-substituted with J.

When a substituent is monovalent, such as, for example, F or Cl, it isbonded to the atom it is substituting by a single bond. When asubstituent is more than monovalent, such as O, which is divalent, itcan be bonded to the atom it is substituting by more than one bond,i.e., a divalent substituent is bonded by a double bond; for example, aC substituted with O forms a carbonyl group, C═O, which can also bewritten as “CO”, “C(O)”, or “C(═O)”, wherein the C and the O are doublebonded. When a carbon atom is substituted with a double-bonded oxygen(═O) group, the oxygen substituent is termed an “oxo” group. When adivalent substituent such as NR is double-bonded to a carbon atom, theresulting C(═NR) group is termed an “imino” group. When a divalentsubstituent such as S is double-bonded to a carbon atom, the resultsC(═S) group is termed a “thiocarbonyl” or “thiono” group.

Alternatively, a divalent substituent such as O or S can be connected bytwo single bonds to two different carbon atoms. For example, 0, adivalent substituent, can be bonded to each of two adjacent carbon atomsto provide an epoxide group, or the O can form a bridging ether group,termed an “oxy” group, between adjacent or non-adjacent carbon atoms,for example bridging the 1,4-carbons of a cyclohexyl group to form a[2.2.1]-oxabicyclo system. Further, any substituent can be bonded to acarbon or other atom by a linker, such as (CH₂)_(n) or (CR′₂)_(n)wherein n is 1, 2, 3, or more, and each R′ is independently selected.

C(O) and S(O)₂ groups can also be bound to one or two heteroatoms, suchas nitrogen or oxygen, rather than to a carbon atom. For example, when aC(O) group is bound to one carbon and one nitrogen atom, the resultinggroup is called an “amide” or “carboxamide.” When a C(O) group is boundto two nitrogen atoms, the functional group is termed a “urea.” When aC(O) is bonded to one oxygen and one nitrogen atom, the resulting groupis termed a “carbamate” or “urethane.” When a S(O)₂ group is bound toone carbon and one nitrogen atom, the resulting unit is termed a“sulfonamide.” When a S(O)₂ group is bound to two nitrogen atoms, theresulting unit is termed a “sulfamate.”

Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groupsas well as other substituted groups also include groups in which one ormore bonds to a hydrogen atom are replaced by one or more bonds,including double or triple bonds, to a carbon atom, or to a heteroatomsuch as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester,amide, imide, urethane, and urea groups; and nitrogen in imines,hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.

Substituted ring groups such as substituted cycloalkyl, aryl,heterocyclyl and heteroaryl groups also include rings and fused ringsystems in which a bond to a hydrogen atom is replaced with a bond to acarbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl andheteroaryl groups can also be substituted with alkyl, alkenyl, andalkynyl groups as defined herein.

By a “ring system” as the term is used herein is meant a moietycomprising one, two, three or more rings, which can be substituted withnon-ring groups or with other ring systems, or both, which can be fullysaturated, partially unsaturated, fully unsaturated, or aromatic, andwhen the ring system includes more than a single ring, the rings can befused, bridging, or spirocyclic.

By “spirocyclic” is meant the class of structures wherein two rings arefused at a single tetrahedral carbon atom, as is well known in the art.

As to any of the groups described herein, which contain one or moresubstituents, it is understood, of course, that such groups do notcontain any substitution or substitution patterns which are stericallyimpractical and/or synthetically non-feasible. In addition, thecompounds of this disclosed subject matter include all stereochemicalisomers arising from the substitution of these compounds.

Alkyl groups include straight chain and branched alkyl groups andcycloalkyl groups having from 1 to about 20 carbon atoms, and typicallyfrom 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.Examples of straight chain alkyl groups include those with from 1 to 8carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl,n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groupsinclude, but are not limited to, isopropyl, iso-butyl, sec-butyl,t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As usedherein, the term “alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkylgroups as well as other branched chain forms of alkyl. Representativesubstituted alkyl groups can be substituted one or more times with anyof the groups listed above, for example, amino, hydroxy, cyano, carboxy,nitro, thio, alkoxy, and halogen groups.

Cycloalkyl groups are cyclic alkyl groups such as, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl groups. In some embodiments, the cycloalkyl group can have 3to about 8-12 ring members, whereas in other embodiments the number ofring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groupsfurther include polycyclic cycloalkyl groups such as, but not limitedto, norbomyl, adamantyl, bomyl, camphenyl, isocamphenyl, and carenylgroups, and fused rings such as, but not limited to, decalinyl, and thelike. Cycloalkyl groups also include rings that are substituted withstraight or branched chain alkyl groups as defined above. Representativesubstituted cycloalkyl groups can be mono-substituted or substitutedmore than once, such as, but not limited to, 2,2-, 2,3-, 2,4-2,5- or2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substitutednorbomyl or cycloheptyl groups, which can be substituted with, forexample, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, andhalogen groups. The term “cycloalkenyl” alone or in combination denotesa cyclic alkenyl group.

The terms “carbocyclic,” “carbocyclyl,” and “carbocycle” denote a ringstructure wherein the atoms of the ring are carbon, such as a cycloalkylgroup or an aryl group. In some embodiments, the carbocycle has 3 to 8ring members, whereas in other embodiments the number of ring carbonatoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary,the carbocyclic ring can be substituted with as many as N−1 substituentswherein N is the size of the carbocyclic ring with, for example, alkyl,alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl,heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groupsas are listed above. A carbocyclyl ring can be a cycloalkyl ring, acycloalkenyl ring, or an aryl ring. A carbocyclyl can be monocyclic orpolycyclic, and if polycyclic each ring can be independently be acycloalkyl ring, a cycloalkenyl ring, or an aryl ring.

(Cycloalkyl)alkyl groups, also denoted cycloalkylalkyl, are alkyl groupsas defined above in which a hydrogen or carbon bond of the alkyl groupis replaced with a bond to a cycloalkyl group as defined above.

Alkenyl groups include straight and branched chain and cyclic alkylgroups as defined above, except that at least one double bond existsbetween two carbon atoms. Thus, alkenyl groups have from 2 to about 20carbon atoms, and typically from 2 to 12 carbons or, in someembodiments, from 2 to 8 carbon atoms. Examples include, but are notlimited to vinyl, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂,—C(CH₃)═CH(CH₃), —C(CH₂CH₃)═CH₂, cyclohexenyl, cyclopentenyl,cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

Cycloalkenyl groups include cycloalkyl groups having at least one doublebond between 2 carbons. Thus for example, cycloalkenyl groups includebut are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienylgroups. Cycloalkenyl groups can have from 3 to about 8-12 ring members,whereas in other embodiments the number of ring carbon atoms range from3 to 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkylgroups such as, but not limited to, norbornyl, adamantyl, bornyl,camphenyl, isocamphenyl, and carenyl groups, and fused rings such as,but not limited to, decalinyl, and the like, provided they include atleast one double bond within a ring. Cycloalkenyl groups also includerings that are substituted with straight or branched chain alkyl groupsas defined above.

(Cycloalkenyl)alkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of the alkyl group is replaced with a bond to acycloalkenyl group as defined above.

Alkynyl groups include straight and branched chain alkyl groups, exceptthat at least one triple bond exists between two carbon atoms. Thus,alkynyl groups have from 2 to about 20 carbon atoms, and typically from2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.Examples include, but are not limited to —C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃),—CH₂C≡CH, —CH₂C≡C(CH₃), and —CH₂C≡C(CH₂CH₃) among others.

The term “heteroalkyl” by itself or in combination with another termmeans, unless otherwise stated, a stable straight or branched chainalkyl group consisting of the stated number of carbon atoms and one ortwo heteroatoms selected from the group consisting of O, N, and S, andwherein the nitrogen and sulfur atoms may be optionally oxidized and thenitrogen heteroatom may be optionally quatemized. The heteroatom(s) maybe placed at any position of the heteroalkyl group, including betweenthe rest of the heteroalkyl group and the fragment to which it isattached, as well as attached to the most distal carbon atom in theheteroalkyl group. Examples include: —O—CH₂—CH₂—CH₃, —CH₂—CH₂CH₂—OH,—CH₂—CH₂—NH—CH₃, —CH₂—S—CH₂—CH₃, —CH₂CH₂—S(═O)—CH₃, and—CH₂CH₂—O—CH₂CH₂—O—CH₃. Up to two heteroatoms may be consecutive, suchas, for example, —CH₂—NH—OCH₃, or —CH₂—CH₂—S—S—CH₃.

A “cycloheteroalkyl” ring is a cycloalkyl ring containing at least oneheteroatom. A cycloheteroalkyl ring can also be termed a “heterocyclyl,”described below.

The term “heteroalkenyl” by itself or in combination with another termmeans, unless otherwise stated, a stable straight or branched chainmonounsaturated or di-unsaturated hydrocarbon group consisting of thestated number of carbon atoms and one or two heteroatoms selected fromthe group consisting of O, N, and S, and wherein the nitrogen and sulfuratoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quaternized. Up to two heteroatoms may be placedconsecutively. Examples include —CH═CH—O—CH₃, —CH═CH—CH₂—OH,—CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —CH₂—CH═CH—CH₂—SH, and and—CH═CH—O—CH₂CH₂—O—CH₃.

Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms in the ring. Thus aryl groups include, but are not limitedto, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl,phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl,biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments,aryl groups contain about 6 to about 14 carbons in the ring portions ofthe groups. Aryl groups can be unsubstituted or substituted, as definedabove. Representative substituted aryl groups can be mono-substituted orsubstituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-,or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can besubstituted with carbon or non-carbon groups such as those listed above.

Aralkyl groups are alkyl groups as defined above in which a hydrogen orcarbon bond of an alkyl group is replaced with a bond to an aryl groupas defined above. Representative aralkyl groups include benzyl andphenylethyl groups and fused (cycloalkylaryl)alkyl groups such as4-ethyl-indanyl. Aralkenyl group are alkenyl groups as defined above inwhich a hydrogen or carbon bond of an alkyl group is replaced with abond to an aryl group as defined above.

Heterocyclyl groups or the term “heterocyclyl” includes aromatic andnon-aromatic ring compounds containing 3 or more ring members, of which,one or more is a heteroatom such as, but not limited to, N, O, and S.Thus a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or ifpolycyclic, any combination thereof. In some embodiments, heterocyclylgroups include 3 to about 20 ring members, whereas other such groupshave 3 to about 15 ring members. A heterocyclyl group designated as aC₂-heterocyclyl can be a 5-ring with two carbon atoms and threeheteroatoms, a 6-ring with two carbon atoms and four heteroatoms and soforth. Likewise a C₄-heterocyclyl can be a 5-ring with one heteroatom, a6-ring with two heteroatoms, and so forth. The number of carbon atomsplus the number of heteroatoms sums up to equal the total number of ringatoms. A heterocyclyl ring can also include one or more double bonds. Aheteroaryl ring is an embodiment of a heterocyclyl group. The phrase“heterocyclyl group” includes fused ring species including thosecomprising fused aromatic and non-aromatic groups. For example, adioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenylring system) are both heterocyclyl groups within the meaning herein. Thephrase also includes polycyclic ring systems containing a heteroatomsuch as, but not limited to, quinuclidyl. Heterocyclyl groups can beunsubstituted, or can be substituted as discussed above. Heterocyclylgroups include, but are not limited to, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl,benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl,indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl,thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinylgroups. Representative substituted heterocyclyl groups can bemono-substituted or substituted more than once, such as, but not limitedto, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or6-substituted, or disubstituted with groups such as those listed above.

Heteroaryl groups are aromatic ring compounds containing 5 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12ring members. A heteroaryl group is a variety of a heterocyclyl groupthat possesses an aromatic electronic structure. A heteroaryl groupdesignated as a C₂-heteroaryl can be a 5-ring with two carbon atoms andthree heteroatoms, a 6-ring with two carbon atoms and four heteroatomsand so forth. Likewise a C₄-heteroaryl can be a 5-ring with oneheteroatom, a 6-ring with two heteroatoms, and so forth. The number ofcarbon atoms plus the number of heteroatoms sums up to equal the totalnumber of ring atoms. Heteroaryl groups include, but are not limited to,groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl,benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroarylgroups can be unsubstituted, or can be substituted with groups as isdiscussed above. Representative substituted heteroaryl groups can besubstituted one or more times with groups such as those listed above.

Additional examples of aryl and heteroaryl groups include but are notlimited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl),N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl,anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl(2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl,isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl,acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl),imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl),triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl(1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl),7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl(2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl),2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl),3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl),5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl),7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl),benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl(1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl),5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl,5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl,5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl),10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

Heterocyclylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group as defined above is replacedwith a bond to a heterocyclyl group as defined above. Representativeheterocyclyl alkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-ylethyl, and indol-2-yl propyl.

Heteroarylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheteroaryl group as defined above.

The term “alkoxy” refers to an oxygen atom connected to an alkyl group,including a cycloalkyl group, as are defined above. Examples of linearalkoxy groups include but are not limited to methoxy, ethoxy, propoxy,butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxyinclude but are not limited to isopropoxy, sec-butoxy, tert-butoxy,isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxyinclude but are not limited to cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can includeone to about 12-20 carbon atoms bonded to the oxygen atom, and canfurther include double or triple bonds, and can also includeheteroatoms. For example, an allyloxy group is an alkoxy group withinthe meaning herein. A methoxyethoxy group is also an alkoxy group withinthe meaning herein, as is a methylenedioxy group in a context where twoadjacent atoms of a structures are substituted therewith.

The terms “halo” or “halogen” or “halide” by themselves or as part ofanother substituent mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom, preferably, fluorine, chlorine, or bromine.

A “haloalkyl” group includes mono-halo alkyl groups, poly-halo alkylgroups wherein all halo atoms can be the same or different, and per-haloalkyl groups, wherein all hydrogen atoms are replaced by halogen atoms,such as fluoro. Examples of haloalkyl include trifluoromethyl,1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl,perfluorobutyl, and the like.

A “haloalkoxy” group includes mono-halo alkoxy groups, poly-halo alkoxygroups wherein all halo atoms can be the same or different, and per-haloalkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms,such as fluoro. Examples of haloalkoxy include trifluoromethoxy,1,1-dichloroethoxy, 1,2-dichloroethoxy, 1,3-dibromo-3,3-difluoropropoxy,perfluorobutoxy, and the like.

The term “(C_(x)-C_(y))perfluoroalkyl,” wherein x<y, means an alkylgroup with a minimum of x carbon atoms and a maximum of y carbon atoms,wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is—(C₁-C₆)perfluoroalkyl, more preferred is —(C₁-C₃)perfluoroalkyl, mostpreferred is —CF₃.

The term “(C_(x)-C_(y))perfluoroalkylene,” wherein x<y, means an alkylgroup with a minimum of x carbon atoms and a maximum of y carbon atoms,wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is—(C₁-C₆)perfluoroalkylene, more preferred is —(C₁-C₃)perfluoroalkylene,most preferred is —CF₂—.

The terms “aryloxy” and “arylalkoxy” refer to, respectively, an arylgroup bonded to an oxygen atom and an aralkyl group bonded to the oxygenatom at the alkyl moiety. Examples include but are not limited tophenoxy, naphthyloxy, and benzyloxy.

An “acyl” group as the term is used herein refers to a group containinga carbonyl moiety wherein the group is bonded via the carbonyl carbonatom. The carbonyl carbon atom is also bonded to another carbon atom,which can be part of an alkyl, aryl, aralkyl cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl group or the like. In the special case wherein thecarbonyl carbon atom is bonded to a hydrogen, the group is a “formyl”group, an acyl group as the term is defined herein. An acyl group caninclude 0 to about 12-20 additional carbon atoms bonded to the carbonylgroup. An acyl group can include double or triple bonds within themeaning herein. An acryloyl group is an example of an acyl group. Anacyl group can also include heteroatoms within the meaning here. Anicotinoyl group (pyridyl-3-carbonyl) group is an example of an acylgroup within the meaning herein. Other examples include acetyl, benzoyl,phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and thelike. When the group containing the carbon atom that is bonded to thecarbonyl carbon atom contains a halogen, the group is termed a“haloacyl” group. An example is a trifluoroacetyl group.

The term “amine” includes primary, secondary, and tertiary amineshaving, e.g., the formula N(group)₃ wherein each group can independentlybe H or non-H, such as alkyl, aryl, and the like. Amines include but arenot limited to R—NH₂, for example, alkylamines, arylamines,alkylarylamines; R₂NH wherein each R is independently selected, such asdialkylamines, diarylamines, aralkylamines, heterocyclylamines and thelike; and R₃N wherein each R is independently selected, such astrialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, andthe like. The term “amine” also includes ammonium ions as used herein.

An “amino” group is a substituent of the form —NH₂, —NHR, —NR₂, —NR₃ ⁺,wherein each R is independently selected, and protonated forms of each,except for —NR₃ ⁺, which cannot be protonated. Accordingly, any compoundsubstituted with an amino group can be viewed as an amine. An “aminogroup” within the meaning herein can be a primary, secondary, tertiaryor quaternary amino group. An “alkylamino” group includes amonoalkylamino, dialkylamino, and trialkylamino group.

An “ammonium” ion includes the unsubstituted ammonium ion NH₄ ⁺, butunless otherwise specified, it also includes any protonated orquaternarized forms of amines. Thus, trimethylammonium hydrochloride andtetramethylammonium chloride are both ammonium ions, and amines, withinthe meaning herein.

The term “amide” (or “amido”) includes C- and N-amide groups, i.e.,—C(O)NR₂, and —NRC(O)R groups, respectively. Amide groups thereforeinclude but are not limited to primary carboxamide groups (—C(O)NH₂) andformamide groups (—NHC(O)H). A “carboxamido” group is a group of theformula C(O)NR₂, wherein R can be H, alkyl, aryl, etc.

The term “azido” refers to an N₃ group. An “azide” can be an organicazide or can be a salt of the azide (N₃ ⁻) anion. The term “nitro”refers to an NO₂ group bonded to an organic moiety. The term “nitroso”refers to an NO group bonded to an organic moiety. The term nitraterefers to an ONO₂ group bonded to an organic moiety or to a salt of thenitrate (NO₃ ⁻) anion.

The term “urethane” (“carbamoyl” or “carbamyl”) includes N- andO-urethane groups, i.e., —NRC(O)OR and —OC(O)NR₂ groups, respectively.

The term “sulfonamide” (or “sulfonamido”) includes S- and N-sulfonamidegroups, i.e., —SO₂NR₂ and —NRSO₂R groups, respectively. Sulfonamidegroups therefore include but are not limited to sulfamoyl groups(—SO₂NH₂). An organosulfur structure represented by the formula—S(O)(NR)— is understood to refer to a sulfoximine, wherein both theoxygen and the nitrogen atoms are bonded to the sulfur atom, which isalso bonded to two carbon atoms.

The term “amidine” or “amidino” includes groups of the formula—C(NR)NR₂. Typically, an amidino group is —C(NH)NH₂.

The term “guanidine” or “guanidino” includes groups of the formula—NRC(NR)NR₂. Typically, a guanidino group is —NHC(NH)NH₂.

Standard abbreviations for chemical groups such as are well known in theart are used; e.g., Me=methyl, Et=ethyl, i-Pr=isopropyl, Bu=butyl,t-Bu=tert-butyl, Ph=phenyl, Bn=benzyl, Ac=acetyl, Bz=benzoyl,Boc=tert-butoxycarbonyl, and the like.

A “salt” as is well known in the art includes an organic compound suchas a carboxylic acid, a sulfonic acid, or an amine, in ionic form, incombination with a counterion. For example, acids in their anionic formcan form salts with cations such as metal cations, for example sodium,potassium, and the like; with ammonium salts such as NH₄ ⁺ or thecations of various amines, including tetraalkyl ammonium salts such astetramethylammonium, or other cations such as trimethylsulfonium, andthe like. A “pharmaceutically acceptable” or “pharmacologicallyacceptable” salt is a salt formed from an ion that has been approved forhuman consumption and is generally non-toxic, such as a chloride salt ora sodium salt. A “zwitterion” is an internal salt such as can be formedin a molecule that has at least two ionizable groups, one forming ananion and the other a cation, which serve to balance each other. Forexample, amino acids such as glycine can exist in a zwitterionic form. A“zwitterion” is a salt within the meaning herein. The compounds of thepresent invention may take the form of salts. The term “salts” embracesaddition salts of free acids or free bases which are compounds of theinvention. Salts can be “pharmaceutically-acceptable salts.” The term“pharmaceutically-acceptable salt” refers to salts which possesstoxicity profiles within a range that affords utility in pharmaceuticalapplications. Pharmaceutically unacceptable salts may nonethelesspossess properties such as high crystallinity, which have utility in thepractice of the present invention, such as for example utility inprocess of synthesis, purification or formulation of compounds of theinvention.

Suitable pharmaceutically-acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic,sulfuric, and phosphoric acids. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric,salicylic, galactaric and galacturonic acid. Examples ofpharmaceutically unacceptable acid addition salts include, for example,perchlorates and tetrafluoroborates.

Suitable pharmaceutically acceptable base addition salts of compounds ofthe invention include, for example, metallic salts including alkalimetal, alkaline earth metal and transition metal salts such as, forexample, calcium, magnesium, potassium, sodium and zinc salts.Pharmaceutically acceptable base addition salts also include organicsalts made from basic amines such as, for example,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples ofpharmaceutically unacceptable base addition salts include lithium saltsand cyanate salts. Although pharmaceutically unacceptable salts are notgenerally useful as medicaments, such salts may be useful, for exampleas intermediates in the synthesis of Formula (I) compounds, for examplein their purification by recrystallization. All of these salts may beprepared by conventional means from the corresponding compound accordingto Formula (I) by reacting, for example, the appropriate acid or basewith the compound according to Formula (I). The term “pharmaceuticallyacceptable salts” refers to nontoxic inorganic or organic acid and/orbase addition salts, see, for example, Lit et al., Salt Selection forBasic Drugs (1986), Int J. Pharm., 33, 201-217, incorporated byreference herein.

A “hydrate” is a compound that exists in a composition with watermolecules. The composition can include water in stoichiometricquantities, such as a monohydrate or a dihydrate, or can include waterin random amounts. As the term is used herein a “hydrate” refers to asolid form, i.e., a compound in water solution, while it may behydrated, is not a hydrate as the term is used herein.

A “solvate” is a similar composition except that a solvent other thatwater replaces the water. For example, methanol or ethanol can form an“alcoholate”, which can again be stoichiometric or non-stoichiometric.As the term is used herein a “solvate” refers to a solid form, i.e., acompound in solution in a solvent, while it may be solvated, is not asolvate as the term is used herein.

A “prodrug” as is well known in the art is a substance that can beadministered to a patient where the substance is converted in vivo bythe action of biochemicals within the patients body, such as enzymes, tothe active pharmaceutical ingredient. Examples of prodrugs includeesters of carboxylic acid groups, which can be hydrolyzed by endogenousesterases as are found in the bloodstream of humans and other mammals.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

In addition, where features or aspects of the invention are described interms of Markush groups, those skilled in the art will recognize thatthe invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group. For example, if X isdescribed as selected from the group consisting of bromine, chlorine,and iodine, claims for X being bromine and claims for X being bromineand chlorine are fully described. Moreover, where features or aspects ofthe invention are described in terms of Markush groups, those skilled inthe art will recognize that the invention is also thereby described interms of any combination of individual members or subgroups of membersof Markush groups. Thus, for example, if X is described as selected fromthe group consisting of bromine, chlorine, and iodine, and Y isdescribed as selected from the group consisting of methyl, ethyl, andpropyl, claims for X being bromine and Y being methyl are fullydescribed.

If a value of a variable that is necessarily an integer, e.g., thenumber of carbon atoms in an alkyl group or the number of substituentson a ring, is described as a range, e.g., 0-4, what is meant is that thevalue can be any integer between 0 and 4 inclusive, i.e., 0, 1, 2, 3, or4.

In various embodiments, the compound or set of compounds, such as areused in the inventive methods, can be any one of any of the combinationsand/or sub-combinations of the above-listed embodiments.

In various embodiments, a compound as shown in any of the Examples, oramong the exemplary compounds, is provided. Provisos may apply to any ofthe disclosed categories or embodiments wherein any one or more of theother above disclosed embodiments or species may be excluded from suchcategories or embodiments.

The present invention further embraces isolated compounds of theinvention. The expression “isolated compound” refers to a preparation ofa compound of the invention, or a mixture of compounds the invention,wherein the isolated compound has been separated from the reagents used,and/or byproducts formed, in the synthesis of the compound or compounds.“Isolated” does not mean that the preparation is technically pure(homogeneous), but it is sufficiently pure to compound in a form inwhich it can be used therapeutically. Preferably an “isolated compound”refers to a preparation of a compound of the invention or a mixture ofcompounds of the invention, which contains the named compound or mixtureof compounds of the invention in an amount of at least 10 percent byweight of the total weight. Preferably the preparation contains thenamed compound or mixture of compounds in an amount of at least 50percent by weight of the total weight; more preferably at least 80percent by weight of the total weight; and most preferably at least 90percent, at least 95 percent or at least 98 percent by weight of thetotal weight of the preparation.

The compounds of the invention and intermediates may be isolated fromtheir reaction mixtures and purified by standard techniques such asfiltration, liquid-liquid extraction, solid phase extraction,distillation, recrystallization or chromatography, including flashcolumn chromatography, or HPLC.

Isomerism and Tautomerism in Compounds of the Invention

Tautomerism

Within the present invention it is to be understood that a compound ofthe formula (I) or a salt thereof may exhibit the phenomenon oftautomerism whereby two chemical compounds that are capable of facileinterconversion by exchanging a hydrogen atom between two atoms, toeither of which it forms a covalent bond. Since the tautomeric compoundsexist in mobile equilibrium with each other they may be regarded asdifferent isomeric forms of the same compound. It is to be understoodthat the formulae drawings within this specification can represent onlyone of the possible tautomeric forms. However, it is also to beunderstood that the invention encompasses any tautomeric form, and isnot to be limited merely to any one tautomeric form utilized within theformulae drawings. The formulae drawings within this specification canrepresent only one of the possible tautomeric forms and it is to beunderstood that the specification encompasses all possible tautomericforms of the compounds drawn not just those forms which it has beenconvenient to show graphically herein. For example, tautomerism may beexhibited by a pyrazolyl group bonded as indicated by the wavy line.While both substituents would be termed a 4-pyrazolyl group, it isevident that a different nitrogen atom bears the hydrogen atom in eachstructure.

Such tautomerism can also occur with substituted pyrazoles such as3-methyl, 5-methyl, or 3,5-dimethylpyrazoles, and the like. Anotherexample of tautomerism is amido-imido (lactam-lactim when cyclic)tautomerism, such as is seen in heterocyclic compounds bearing a ringoxygen atom adjacent to a ring nitrogen atom. For example, theequilibrium:

is an example of tautomerism. Accordingly, a structure depicted hereinas one tautomer is intended to also include the other tautomer.Optical Isomerism

It will be understood that when compounds of the present inventioncontain one or more chiral centers, the compounds may exist in, and maybe isolated as pure enantiomeric or diastereomeric forms or as racemicmixtures. The present invention therefore includes any possibleenantiomers, diastereomers, racemates or mixtures thereof of thecompounds of the invention.

The isomers resulting from the presence of a chiral center comprise apair of non-superimposable isomers that are called “enantiomers.” Singleenantiomers of a pure compound are optically active, i.e., they arecapable of rotating the plane of plane polarized light. Singleenantiomers are designated according to the Cahn-Ingold-Prelog system.The priority of substituents is ranked based on atomic weights, a higheratomic weight, as determined by the systematic procedure, having ahigher priority ranking. Once the priority ranking of the four groups isdetermined, the molecule is oriented so that the lowest ranking group ispointed away from the viewer. Then, if the descending rank order of theother groups proceeds clockwise, the molecule is designated (R) and ifthe descending rank of the other groups proceeds counterclockwise, themolecule is designated (S). In the example in Scheme 14, theCahn-Ingold-Prelog ranking is A>B>C>D. The lowest ranking atom, D isoriented away from the viewer.

The present invention is meant to encompass diastereomers as well astheir racemic and resolved, diastereomerically and enantiomerically pureforms and salts thereof. Diastereomeric pairs may be resolved by knownseparation techniques including normal and reverse phase chromatography,and crystallization. A racemic mixture, or a racemate, is a mixture oftwo enantiomers.

“Isolated optical isomer” means a compound which has been substantiallypurified from the corresponding optical isomer(s) of the same formula.Preferably, the isolated isomer is at least about 80%, more preferablyat least 90% pure, even more preferably at least 98% pure, mostpreferably at least about 99% pure, by weight.

Isolated optical isomers may be purified from racemic mixtures bywell-known chiral separation techniques. According to one such method, aracemic mixture of a compound of the invention, or a chiral intermediatethereof, is separated into 99% wt. % pure optical isomers by HPLC usinga suitable chiral column, such as a member of the series of DAICEL®CHIRALPAK® family of columns (Daicel Chemical Industries, Ltd., Tokyo,Japan). The column is operated according to the manufacturer'sinstructions.

Cis-Trans Isomerism

Compounds comprising double bonds and having non-identical substituentsat each end of the double bond can exhibit cis-trans, or Z/E, isomerism.Cis-trans isomerism is present when at each terminus of the double bondthere is one hydrogen and one non-hydrogen substituent. Thus, acomopound of formula A-CH═CH—B can exist in two isomeric forms,

In cases where the four substituents are more complex, this type ofisomerism is termed Z/E isomerism. The groups are assigned priority asin the case of optical isomerism, discussed above, and when the twohighest priority groups are cis to each other, the double bond is termeda Z double bond; when the two highest priority groups are trans to eachother, the double bond is termed an E double bond.

Cis and trans isomerism can also be present in ring systems, where freerotation cannot occur. For example, when both compounds are on the same“side” of the ring, the groups are said to be cis to each other, andwhen they are on opposite sides, they are said to be trans to eachother. For example, 1,4-dimethylcyclohexane can exist in cis and transforms:

cis:

when the cyclohexane is depicted the chair conformer,

trans:

when the cyclohexane is depicted the chair conformer,

In certain of the compounds herein, having rings capable of forming cisand trans isomers, compounds are described as cis or trans; thesedesignations refer to ring cis and trans isomerism. When such compoundsare optically active, i.e., possess chiral centers, cis compounds can beracemates, and are termed cis-racemates; or alternatively transcompounds can be racemates, and are termed trans-racemates.

Rotational Isomerism

It is understood that due to chemical properties (i.e., resonancelending some double bond character to the C—N bond) of restrictedrotation about the amide bond linkage (as illustrated below) it ispossible to observe separate rotamer species and even, under somecircumstances, to isolate such species (see below). It is furtherunderstood that certain structural elements, including steric bulk orsubstituents on the amide nitrogen, may enhance the stability of arotamer to the extent that a compound may be isolated as, and existindefinitely, as a single stable rotamer. The present inventiontherefore includes any possible stable rotamers of formula (I) which arebiologically active in the treatment of cancer or other proliferativedisease states.

Regioisomerism

The preferred compounds of the present invention have a particularspatial arrangement of substituents on the aromatic rings, which isrelated to the structure activity relationship demonstrated by thecompound class. Often such substitution arrangement is denoted by anumbering system; however, numbering systems are often not consistentbetween different ring systems. In six-membered aromatic systems, thespatial arrangements are specified by the common nomenclature “para” for1,4-substitution, “meta” for 1,3-substitution and “ortho” for1,2-substitution as shown below.

DESCRIPTION

Compounds of the Invention

In various embodiments, the invention is directed to a compound offormula (I)

wherein

the ring designated A can further comprise an additional nitrogen atomin any position that bears any of W, X, Y, or Z, provided that therespective group W, X, Y, or Z is absent from that position;

W is H, (C1-C6)alkyl, (C1-C6)haloalkyl, hydroxy(C1-C6)alkyl,(C3-C9)cycloalkyl, or halo;

X is H, halo, nitro, (C1-C6)alkyl, (C1-C6)haloalkyl,hydroxy(C1-C6)alkyl, (C3-C9)cycloalkyl, NR^(a)R^(b),N(R^(a))C(═O)(C1-C6)alkyl, CO₂R, or heteroaryl;

Y is H, halo, (C1-C6)alkyl, (C3-C9)cycloalkyl, or halo;

Z is halo, hydroxy, CO₂R, C(═O)NR₂, CN, heteroaryl(C₀-C₆)alkyl,hydroxy(C1-C6)alkyl, HC(═O), HC(═O), (C1-C6)C(═O), or CR(═NOR);

wherein each independently selected R is H, (C1-C6)alkyl,(C3-C9)cycloalkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C6)alkyl;

or, any adjacent pair of W, X, and Y, can together with the atoms towhich they are bonded form a fused cycloalkyl, heterocyclyl, or aryl, orheteroaryl, any of which can be mono- or independently multi-substitutedwith (C1-C6)alkyl, (C3-C9)cycloalkyl, halo, nitro, NR^(a)R^(b),N(R^(a))C(═O)(C1-C6)alkyl, CO₂R, or heteroaryl;

wherein any alkyl, cycloalkyl, aryl, or heteroaryl of W, X, Y, or Z, canbe unsubstituted or can be mono- or independently multi-substituted with(C1-C6)alkyl, (C3-C9)cycloalkyl, halo, nitro, NR^(a)R^(b),N(R^(a))C(═O)(C1-C6)alkyl, CO₂R, or heteroaryl;

the ring system Cyc, comprising the nitrogen atom, comprises a mono-,bi-, or tri-cyclic heterocyclyl bonded to ring A via the nitrogen atom,wherein Cyc comprises a 4, 5, 6, 7, or 8 membered ring, optionallybridged with one or two bridges independently comprising 0, 1, or 2carbon atoms, the ring system Cyc optionally containing 1 or 2additional heteroatoms selected from NR, O, or S(O)_(q) wherein q=0, 1,or 2; wherein R′, and optionally, m independently selected R², arebonded to the ring system Cyc, m=0, 1, or 2;

R¹ is (CH₂)_(n)NR^(a)R^(b), wherein R^(a) and R^(b) are eachindependently H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, orheterocyclylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, or heterocyclylalkyl, is substituted with 0, 1, 2, 3, or 4independently selected J, and wherein any heterocyclyl or cycloalkyl ismono-, bi-, or tri-cyclic; or R^(a) and R^(b) together with the nitrogenatom to which they are bonded form a heterocyclyl ring substituted with0, 1, 2, 3, or 4 independently selected J, wherein n=0, 1, or 2;

or R¹ is (CH₂)_(p1)NR^(a)(CH₂)_(p2) bonded to two carbon atoms of Cyc toform a 5-, 6-, or 7-membered heterocyclyl substituted with 0, 1, 2, 3,or 4 independently selected J, p1 and p2 are independently 0, 1, or 2,provided that p1+p2 is no less than 2;

R² is (C1-C6)alkyl, hydroxy(C1-C6)alkyl, OR, CO₂R, or halo, wherein m=0,1, or 2;

J is independently at each occurrence OR, (C1-C6)alkyl,hydroxy(C1-C6)alkyl, (C3-C9)cycloalkyl, CO₂R, or halo;

or any pharmaceutically acceptable salt thereof.

In various embodiments, the ring designated A can be pyridyl,pyridazinyl, pyrimidyl, or pyrazinyl, or can be fused to provide aquinolyl, tetrahydroquinolyl, quinoxalinyl, or6,7-dihydro-5H-cyclopenta[b]pyridinyl, any of which can be substitutedor unsubstituted.

In various embodiments of a compound of the invention, W can be H ormethyl.

In various embodiments of a compound of the invention, X can be H,methyl, ethyl, cyclopropyl, bromo, chloro, fluoro, iodo,trifluoromethyl, nitro, amino, acetamido, butyramido, methoxycarbonyl,ethoxycarbonyl, or oxadiazolyl (substituted or unsubstituted).

In various embodiments of a compound of the invention, Y can be H orchloro.

In various embodiments of a compound of the invention, Z can bemethoxycarbonyl, ethoxycarbonyl, hydroxymethyl, formyl, acetyl,O-methylformaldoxime (cis or trans), O-ethylformaldoxime (cis or trans),oxadiazolyl (substituted (alkyl, cycloalkyl) or unsubstituted),pyridazinyl (substituted (alkyl) or unsubstituted), or pyrimidinyl(substituted (alkyl) or unsubstituted).

In various embodiments of a compound of the invention, ring system Cycis any one of

wherein R¹ and, optionally, (R²)m, are bonded thereto at any position,and wherein a wavy line indicates a point of bonding.

In various embodiments of a compound of the invention, R¹ is(CH₂)_(n)NR^(a)R^(b) and n is 0 or 1; R^(a) is ethyl, 2-pentyl,4-methyl-2-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bornyl, adamantyl, or tetrahydropyranyl, any of which is substitutedwith 0, 1, 2, 3, or 4 J, and R^(b) is H.

In various embodiments of a compound of the invention, R¹ is(CH₂)_(n)NR^(a)R^(b) and n is 0 or 1; and R^(a) and R^(b) together withthe nitrogen atom to which they are bonded form a pyrrolidinyl,piperidinyl, azepinyl morpholinyl, or thiomorpholinyl ring, any of whichis substituted with 0, 1, 2, 3, or 4 J.

In various embodiments of a compound of the invention, any R² isindependently selected OR, F, Cl, Br, methyl, hydroxymethyl, ethyl, orhydroxyethyl.

In various embodiments of a compound of the invention, R² is notpresent.

In various embodiments of a compound of the invention, ring system Cycand R¹ together form a group of formula

wherein R^(a) is as defined in herein and a wavy line indicates a pointof bonding, and wherein Cyc is optionally substituted with additional R²groups.

In various embodiments of a compound of the invention, the compound isany of those shown in Table 1, below. A cutoff of IC₅₀ >10 μM was chosento differentiate compounds with potential as medicinal compounds fortreatment of conditions in patients wherein inhibition of the kappaopioid receptor are medically indicated from comparative compounds thatare largely inactive in this assay, and thus are not expected to besuitable candidates for development of medicinal molecular entities. InTable 1, compounds disclosed and claimed herein are provided with anindexing number, and inactive compounds are designated as “C#” forpurposes of identification.

The methods of determining the IC₅₀ values of the compounds are providedbelow.

As is well known in the art, identification of a compound that performswell in an enzyme assay is only a first step in developing a medicinalmolecular entity. For example, the candidate compound must meetstandards for absorption, distribution, metabolism, excretion, andtoxicity (ADMET) in the mammalian body. The inventors herein do notassert that each and every compound disclosed and claimed is a medicinalmolecular entity, but that it is a candidate identified for furtherstudy in the development of a medicinal molecular entity.

TABLE I Compounds of the Invention IC₅₀ nM (% inhib if other Cpd. #Structure than 50%)  1

231  2

4500 (65%)  3

287  6

9200 (80%)  7

133  8

579 C1

NA C2

NA C5

NA C6

NA  10

652  11

2800 C7

NA C8

NA C9

NA  12

765 C10

NA C11

NA  13

621  14

185  15

7700  16

536  17

6800 C12

NA  18

2100  19

2700  20

110  21

317  22

10000  23

854  24

120  25

1200  26

267  27

473  28

387 C13

NA C14

NA C15

NA C16

NA  31

3500  32

5300 C17

NA  33

16  34

5200 (85%)  35

88  36

79  37

142  38

128  39

398 C18

NA C19

NA  40

159  41

331  42

18  43

52  44

79  45

164  46

25  47

2800  48

459  49

1300  50

1000  51

3000  52

3400  53

5600  54

559  55

1800  56

7000  57

2200  58

419  59

36  60

68  61

54  62

2700  63

234  64

901 C20

NA C21

NA  65

2300  66

1700 C22

NA  67

1400 C23

NA C24

NA C25

NA  68

40  69

53 C26

NA  70

110  71

93  72

6600  73

205 C27

21000  74

58  75

36 C28

NA  76

11300  77

11  78

1200  79

25  80

87  81

126  82

127  83

5900  84

6200  85

1800 C29

NA  86

628 C30

NA  87

19000 C31

NA C32

NA  88

52  89

116  90

186  91

198  92

2600  93

621  94

61 C33

NA  95

1.4 C34

NA C35

17000 C36

17000 C37

NA C38

NA C39

NA C40

NA C41

NA C42

NA C43

15000 C44

NA  96

6700  97

2000  98

1100  99

4500 C45

NA C46

NA 100

292 101

4000 C47

NA 102

13000 103

137 104

2200 C48

NA C49

17000 105

56 C50

NA 106

24 107

11000 108

404 109

198 110

108 C51

>20000 C52

>20000 C53

13000 C54

>20000 111

281 C55

>20000 C56

>20000 C57

>20000 112

714 C58

>20000 113

2000 114

1200 115

1700 116

793 117

3800 118

661 C59

>20000 119

12 120

16 121

45 122

125 123

11 124

31 125

41 126

112 127

33 128

35 129

799 130

22 131

30 132

4000 133

272 134

23 C60

14000 135

1630 136

49 137

1600 138

3200 139

4800 140

54 141

107 142

125 143

100 144

4800 C61

10000 145

117 146

85 147

206 148

5800 149

5400 150

9100 151

2100 152

30 153

191 154

146 C62

NA C63

NA C64

NA C65

NA 155

1300 C66

17000 156

1000 157

37 158

431 159

35 160

209 161

157 162

1400 163

915 164

62 165

19 166

32 167

19 168

7000 169

2500 170

11.7 171

1100 172

22 173

1200 174

180 175

46 C67

37000 C68

>20000 176

28 177

>20 178

483 179

253 180

7 181

30 182

76 183

280 184

19 185

24 186

5 187

341 188

187 189

125 190

57 191

420 192

199 193

729 194

180 195

700 196

414 197

85 198

98 199

59 200

14 201

116 202

187 203

132 204

52 205

17 206

33 207

276 208

76 209

18 210

72 211

74 212

267 213

8.5 214

3 215

3 216

4500 217

361 218

475 C69

30000 C70

17000 219

3.5 220

101 221

24 222

163 223

13 224

17 225

70 226

107 227

7 228

21 229

5 230

9 231

0.86 232

8 233

2 234

596 235

4 236

20 237

8 238

38 239

16 240

14 241

59 242

26 243

22 244

566 245

79 246

51 247

4 248

11 249

9 250

8 251

11 252

12 253

10 254

8 255

10 256

631 257

930 C71

NA 258

7160 259

372 C72

NA 260

261 261

1470 C73

NA C74

NA C75

NA 262

60 C76

NA C77

NA C78

NA C79

NA C80

NA C81

NA C82

NA C83

47000 263

1770 264

56 265

49 266

1740 267

180 C84

NA 268

37 269

30 270

4470 271

419 C85

NA C86

NA 272

8700 273

387 C87

NA 274

50 C88

NA 275

98 276

18 277

9 278

4725 279

96 C89

NA 280

99 281

30 282

38 283

4 284

20 285

7 286

298 288

15 289

184 290

47 291

18 292

33 293

20 294

0.7 295

2 296

10 297

2 298

3 299

25 300

16 301

38 302

274 303

0.5 304

3.5 305

17 306

107 307

41 308

2.5 309

0.5 310

4 311

1 312

0.7 313

1.5 314

2 315

4 C90

NA 316

23 317

27 318

19 319

21 320

170 321

105 322

16 323

1340 324

1.3 325

8 326

1.9 327

5.6 328

0.72 329

12.2 330

4.9 331

27 332

19 333

6.6 334

161 335

113 C91

17700 336

4360 337

0.73 338

0.99 339

29 340

6 341

76 342

48 343

10.6 344

16.8 345

104 346

137 347

32 348

1.3 349

21 350

0.97 351

3 352

3.1 353

23 354

4.2 355

1.2 356

12.5 357

22.3 358

9 C92

58000 359

160 C93

10181 360

8 361

1440 362

3 363

10 364

18 365

8 366

19 367

2 368

7 369

2 370

37 371

1 372

15 373

63 374

45 375

12 376

14 377

69 378

256 379

525 380

128 381

860 382

83 383

1161 384

16700 385

1 386

31 387

89 388

20 389

153 390

1920 391

105 392

2960 393

346 394

161 395

49 396

2263 397

1280 398

18 399

953 400

279 401

67 402

16 403

322 404

63 405

21400 406

7680 407

341 408

57 409

129 410

78 411

10 412

476 413

22 414

9 415

3 416

4 417

105 418

50 419

2 420

3 421

48 422

106 423

191 424

422 425

60 426

1970 427

4600 428

101 429

214 430

1000 431

22 432

22 433

7 434

43 435

6 436

26 437

17 438

75 439

231 440

70 441

392 442

324 443

33 444

634 445

55 446

72 447

1150 448

226 449

129 450

11 451

94 452

47 453

85 454

783 455

1640 456

6 457

24 458

440 459

15 460

141 461

52 462

320 463

54 464

87 465

18 466

24 467

431 468

175 469

440 470

40 471

170 472

105 473

3210 474

1900 475

101 476

430 477

42 478

900 479

211 480

8 481

10 482

75 483

315 484

347 485

673 486

1070 487

15 488

19 489

616 490

248 491

33 492

74 493

132 494

64 495

13 496

54 497

48 498

33 499

116 500

423 501

331 502

3109 503

74 504

45 505

126 506

48 507

43 508

5 509

30 510

115 511

227 512

12 513

27 514

55 515

7 516

564 517

1142 518

410 519

95 520

19 521

278 522

67 523

7 524

57 525

17 526

49 527

20 528

23 529

369 530

5100 531

996 532

334 533

263 534

600 535

465 536

19 537

12 538

970 539

3700 540

16 541

45 542

32 543

32 544

10 Me = methyl, Et = ethyl, Boc = t-butoxycarbonyl, Ph = phenyl, iPr =isopropyl, straight or wavy line = either stereochemical option unlessotherwise specified, bold line or solid wedge = bond “up”, hashed lineor hashed wedge = bond “down”, Cis-rac = racemic mixture of two cisisomers. Trans-rac = racemic mixture of two trans isomers. NA = notactive at concentrations up to 10 μM. C# = comparative compound, IC50 >10 μMMethods of Synthesis

The following abbreviations are used throughout this document.

-   Ac acetyl-   AcOH acetic acid-   Boc tert-Butoxycarbonyl-   Bn benzyl-   Bz benzoyl-   BOP Benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium    hexafluorophosphate-   Cbz benzyloxycarbonyl-   CC column chromatography-   CDI Carbonyl diimidazole-   DBU Diazabicycloundecane-   DCM Dichloromethane-   DIAD Diisopropylazodicarboxylate-   DIPEA, ^(i)Pr₂EtN N,N-Diisopropylethylamine-   DMAP 4-(N,N-dimethylamino)pyridine-   DMF N,N-Dimethylformamide-   DMSO Dimethylsulfoxide-   EDAC, EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide    hydrochloride-   eq, equiv Equivalents-   Et₂O Diethyl ether-   EtOAc Ethyl acetate-   h, hr Hours-   HATU O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium PF₆ ⁻-   HCl Hydrochloric acid-   HOAT Hydroxyazabenztriazole-   HOBt Hydroxybenzotriazole-   LiHDMS Lithium hexamethyldisilazide-   LiOH Lithium hydroxide-   mg Milligrams-   min Minutes-   mL Milliliters-   μL Microliters-   mM millimolar-   μM micromolar-   μw microwave heating-   nM nanomolar-   mmole Millimoles-   MS Mass spectroscopy-   MeOH Methanol-   NaBH₃CN Sodium cyanoborohydride-   NaH Sodium hydride-   NaIO₄ Sodium periodate-   NMM N-Methylmorpholine-   rb Round-bottom-   RT Room temperature-   sat. Saturated-   TEA Triethylamine-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   ˜ approximately (˜10° C.) or, to (range, e.g., X˜Y=X to Y)

Example 1. Synthesis of Compound 5

In a capped microwave vial, a mixture of N-Boc-4aminopiperidine I,epoxide II, and Bi(OTf)₃.4H₂O was heated at 150° C. for 30 min undermicrowave irradiation. Upon addition of ethyl ether, the reactionmixture was stirred for 5 minutes, then filtered over celite, washedwith ethyl ether and concentrated under vacuum. The residue wasdissolved in ethyl acetate and washed with brine (2×).

To the product N-Boc-protected aminoalcohol dissolved in CH₂Cl₂ wasadded TFA at room temperature. The reaction mixture was stirred for 30min, then concentrated under reduced pressure. The residue was dissolvedin 1M NaOH and the product extracted with EtOAc (5×). The organic phasewas dried over sodium sulfate and concentrated under reduced pressure.The product was purified by column chromatography (CC) using CH₂Cl₂/MeOHto furnish amino alcohol III.

In a microwave vial a solution of III, pyridine IV and DIPEA in ethanolwas heated at 150° C. for 35 min under microwave irradiation. Theorganic solvent was removed under reduced pressure and the product waspurified by CC using CH₂Cl₂/MeOH to afford Compound 5.

Example 2. Synthesis of Compound 33

To a stirred solution of N-Boc-4aminopiperidine I and cyclohexanone IIin DCE were added NaBH(OAc)₃ and AcOH. The reaction mixture was stirredfor 12 h at room temperature. The mixture was diluted with ethyl acetateand washed with brine (2×). The organic phase was concentrated, and theproduct purified by CC using CH₂Cl₂/MeOH (9:1) furnishing amine III.

To a solution of III in CH₂Cl₂ was added TFA and the reaction mixturewas stirred for 30 min at room temperature. The mixture was concentratedunder reduced pressure, diluted in ethanol followed by addition of DIPEAand pyridine IV. The reaction mixture was heated at 145° C. for 35 minunder microwave irradiation. The crude was concentrated under reducedpressure and the product purified by HPLC furnishing the pure Compound33.

Example 3. Synthesis of Compound 7

In a microwave vial pyridine I, 4-piperidinone ethyl ketal II and DIPEAwere dissolved in ethanol and heated at 125° C. for 45 min undermicrowave irradiation. The organic solvent was removed under reducedpressure and the product was purified by CC using CH₂Cl₂/MeOH to affordthe pyridine derivative III.

A solution of III in THF was added to 5% HCl and heated at 40° C. for 6h. The organic solvent was removed under reduced pressure. The crude wasdissolved in ethyl acetate and washed with 0.5M NaOH (2×). The organicsolvent was dried over sodium sulfate and concentrated under reducedpressure. The product was purified by CC using hexanes/EtOAc to affordthe ketone derivative IV.

To a stirred solution of IV, cyclohexylamine and AcOH in DCE was addedat room temperature NaBH(OAc)₃. The reaction was stirred for 16 h atroom temperature. Upon reaction completion the mixture was diluted inethyl acetate and washed with brine (2×). The organic phase was driedover sodium sulfate and the product purified by CC using CH₂Cl₂/MeOH tofurnish Compound 7.

Example 4. Synthesis of Compound 235

In a microwave vial, a stirring solution of acid XI in 1,4-dioxane wastreated with HOBt and EDCI at room temperature. The reaction was stirredfor 20 min followed by addition, in a single portion, of amidoxime XII.The reaction was stirred for additional 30 min at room temperature andthen heated to 100° C. under microwave irradiation for 35 min. Thereaction mixture was diluted with EtOAc and washed with brine (2×). Theorganic phase was dried over Na₂SO₄ anhydrous and concentrated underreduced pressure. The product was purified by C.C. using CH₂Cl₂:MeOH(99:1) to furnish XIII in 70% yield.

In a microwave vial quinoline XIII, 4-piperidinone ethyl ketal VIII andDIPEA were dissolved in ethanol and heated at 125° C. for 45 min undermicrowave irradiation. The organic solvent was removed under reducedpressure and the product was purified by CC using CH₂Cl₂/MeOH to furnishquinoline XIV in 85% yield.

A solution of XIV in THF was added to 5% HCl and heated at 40° C. for 6h. The solvent was removed under reduced pressure. The crude wasdissolved in EtOAc and washed with 0.5M NaOH (2×). The organic solventwas dried over sodium sulfate and concentrated under reduced pressure.The product XV was purified by CC using hexanes/EtOAc in 62% yield.

To a stirred solution of XV, 4-aminotetrahydropyrane XVI and AcOH in DCEwas added at room temperature NaBH(OAc)₃ and the mixture was stirred for5 h at room temperature. The mixture was diluted in EtOAc and washedwith brine (2×). The organic phase was dried over sodium sulfate and theproduct purified by CC using CH₂Cl₂/MeOH to furnish Compound 235 in 76%yield.

Example 5: Synthesis of 296

To a stirred solution of (3S,4R)piperidine XVII and cyclohexanone in DCEwere added NaBH(OAc)₃ and AcOH and the reaction mixture was stirredovernight at room temperature. The mixture was diluted with ethylacetate and washed with brine (2×). The organic phase was concentrated,and the product purified by CC using CH₂Cl₂/MeOH (9:1) to furnish amineXVIII in 75% yield.

To a solution of XVIII in CH₂Cl₂ was added TFA and the reaction mixturewas stirred for 30 min at room temperature. The mixture was concentratedunder reduced pressure, diluted with EtOAc and washed with NaOH (1M).The aqueous phase was extracted with EtOAc (3×). The organic phase wasconcentrated under reduced pressure and the product XIX was used withoutfurther purification.

In a microwave vial, a solution of XIX, quinoline XIII and DIPEA inethanol was heated at 130° C. for 35 min under microwave irradiation.The crude was concentrated under reduced pressure and the productpurified by HPLC to furnish Compound CYM51427 in 65% yield.

In a microwave vial, a stirring solution of acid XX in 1,4-dioxane wastreated with HOBt and EDCI at room temperature. The reaction was stirredfor 20 min followed by addition, in a single portion, of amidoxime XII.The reaction was stirred for additional 30 min at room temperature andthen heated to 100° C. under microwave irradiation for 35 min. Thereaction mixture was diluted with EtOAc and washed with brine (2×). Theorganic phase was dried over Na₂SO₄ anhydrous and concentrated underreduced pressure. The product XXI was purified by C.C. using CH₂Cl₂:MeOH(99:1).

In a microwave vial pyridine XXI, amine XIX and DIPEA were dissolved inethanol and heated at 145° C. for 2 hours under microwave irradiation.The organic solvent was removed under reduced pressure and the productwas purified by HPLC to furnish CYM51433.

Other compounds of formula (I) can be prepared by the person of ordinaryskill using techniques and approaches described herein in conjunctionwith the chemical literature.

Pharmaceutical Compositions and Uses

Another aspect of an embodiment of the invention provides compositionsof the compounds of the invention, alone or in combination with anothermedicament. As set forth herein, compounds of the invention includestereoisomers, tautomers, solvates, prodrugs, pharmaceuticallyacceptable salts and mixtures thereof. Compositions containing acompound of the invention can be prepared by conventional techniques,e.g. as described in Remington: The Science and Practice of Pharmacy,19th Ed., 1995, or later versions thereof, incorporated by referenceherein. The compositions can appear in conventional forms, for examplecapsules, tablets, aerosols, solutions, suspensions or topicalapplications.

Typical compositions include a compound of the invention and apharmaceutically acceptable excipient which can be a carrier or adiluent. For example, the active compound will usually be mixed with acarrier, or diluted by a carrier, or enclosed within a carrier which canbe in the form of an ampoule, capsule, sachet, paper, or othercontainer. When the active compound is mixed with a carrier, or when thecarrier serves as a diluent, it can be solid, semi-solid, or liquidmaterial that acts as a vehicle, excipient, or medium for the activecompound. The active compound can be adsorbed on a granular solidcarrier, for example contained in a sachet. Some examples of suitablecarriers are water, salt solutions, alcohols, polyethylene glycols,polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin,lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrieror diluent can include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax.

The formulations can be mixed with auxiliary agents which do notdeleteriously react with the active compounds. Such additives caninclude wetting agents, emulsifying and suspending agents, salt forinfluencing osmotic pressure, buffers and/or coloring substancespreserving agents, sweetening agents or flavoring agents. Thecompositions can also be sterilized if desired.

The route of administration can be any route which effectivelytransports the active compound of the invention to the appropriate ordesired site of action, such as oral, nasal, pulmonary, buccal,subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot,subcutaneous, intravenous, intraurethral, intramuscular, intranasal,ophthalmic solution or an ointment, the oral route being preferred.

If a solid carrier is used for oral administration, the preparation canbe tableted, placed in a hard gelatin capsule in powder or pellet formor it can be in the form of a troche or lozenge. If a liquid carrier isused, the preparation can be in the form of a syrup, emulsion, softgelatin capsule or sterile injectable liquid such as an aqueous ornon-aqueous liquid suspension or solution.

Injectable dosage forms generally include aqueous suspensions or oilsuspensions which can be prepared using a suitable dispersant or wettingagent and a suspending agent Injectable forms can be in solution phaseor in the form of a suspension, which is prepared with a solvent ordiluent. Acceptable solvents or vehicles include sterilized water,Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils can be employed as solvents or suspendingagents. Preferably, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the formulation can also be a powder suitable forreconstitution with an appropriate solution as described above. Examplesof these include, but are not limited to, freeze dried, rotary dried orspray dried powders, amorphous powders, granules, precipitates, orparticulates. For injection, the formulations can optionally containstabilizers, pH modifiers, surfactants, bioavailability modifiers andcombinations of these. The compounds can be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection can be in ampoules or inmulti-dose containers.

The formulations of the invention can be designed to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart. Thus, the formulations can also be formulated for controlledrelease or for slow release.

Compositions contemplated by the present invention can include, forexample, micelles or liposomes, or some other encapsulated form, or canbe administered in an extended release form to provide a prolongedstorage and/or delivery effect. Therefore, the formulations can becompressed into pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections. Such implants can employ known inertmaterials such as silicones and biodegradable polymers, e.g.,polylactide-polyglycolide. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides).

For nasal administration, the preparation can contain a compound of theinvention, dissolved or suspended in a liquid carrier, preferably anaqueous carrier, for aerosol application. The carrier can containadditives such as solubilizing agents, e.g., propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives such as parabens.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like are particularly suitable for oral application.Preferable carriers for tablets, dragees, or capsules include lactose,corn starch, and/or potato starch. A syrup or elixir can be used incases where a sweetened vehicle can be employed.

A typical tablet that can be prepared by conventional tablettingtechniques can contain:

Core: Active compound (as free compound or salt thereof)  250 mgColloidal silicon dioxide (Aerosil) ®  1.5 mg Cellulose, microcryst.(Avicel) ®   70 mg Modified cellulose gum (Ac-Di-Sol) ®  7.5 mgMagnesium stearate Ad. Coating: HPMC approx.   9 mg *Mywacett 9-40 Tapprox.  0.9 mg *Acylated monoglyceride used as plasticizer for filmcoating.

A typical capsule for oral administration contains compounds of theinvention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). Themixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule. A typical injectable preparation is produced byaseptically placing 250 mg of compounds of the invention into a vial,aseptically freeze-drying and sealing. For use, the contents of the vialare mixed with 2 mL of sterile physiological saline, to produce aninjectable preparation.

The compounds of the invention can be administered to a mammal,especially a human in need of such treatment, prevention, elimination,alleviation or amelioration of a malcondition. Such mammals include alsoanimals, both domestic animals, e.g. household pets, farm animals, andnon-domestic animals such as wildlife.

The compounds of the invention are effective over a wide dosage range.For example, in the treatment of adult humans, dosages from about 0.05to about 5000 mg, preferably from about 1 to about 2000 mg, and morepreferably between about 2 and about 2000 mg per day can be used. Atypical dosage is about 10 mg to about 1000 mg per day. In choosing aregimen for patients it can frequently be necessary to begin with ahigher dosage and when the condition is under control to reduce thedosage. The exact dosage will depend upon the activity of the compound,mode of administration, on the therapy desired, form in whichadministered, the subject to be treated and the body weight of thesubject to be treated, and the preference and experience of thephysician or veterinarian in charge.

Generally, the compounds of the invention are dispensed in unit dosageform including from about 0.05 mg to about 1000 mg of active ingredienttogether with a pharmaceutically acceptable carrier per unit dosage.

Usually, dosage forms suitable for oral, nasal, pulmonal or transdermaladministration include from about 125 μg to about 1250 mg, preferablyfrom about 250 μg to about 500 mg, and more preferably from about 2.5 mgto about 250 mg, of the compounds admixed with a pharmaceuticallyacceptable carrier or diluent.

Dosage forms can be administered daily, or more than once a day, such astwice or thrice daily. Alternatively dosage forms can be administeredless frequently than daily, such as every other day, or weekly, if foundto be advisable by a prescribing physician.

In various embodiments, the invention is directed to a method ofmodulating a Kappa opioid receptor, comprising contacting the receptorwith an effective amount or concentration of a compound of formula (I)of the invention. For example, the Kappa opioid receptor can be disposedwithin the living tissue of a human. More specifically, the human can besuffering from a dissociative disorder or pain.

In various embodiments, the invention provides a method of treatment ofa dissociative disorder or pain in a patient in need thereof, comprisingadministering to the patient an effective amount or concentration of acompound of formula (I) the invention at a frequency and for a durationto provide a beneficial effect to the patient.

For example, in various embodiments, a method of providingneuroprotection to a patient comprising administering to the patient aneffective amount or concentration of a compound of formula (I) of theinvention, at a frequency and for a duration to provide a beneficialeffect to the patient, is provided.

For example, in various embodiments, a method of modulating the immunesystem in a patient, comprising administering to the patient aneffective amount or concentration of a compound of formula (I) of theinvention, at a frequency and for a duration to provide a beneficialeffect to the patient, is provided.

For example, in various embodiments, a method of inducing diuresis in apatient, comprising administering to the patient an effective amount orconcentration of a compound of formula (I) of the invention, at afrequency and for a duration to provide a beneficial effect to thepatient, is provided.

It is within ordinary skill to evaluate any compound disclosed andclaimed herein for effectiveness in modulation of or binding to a Kappaopioid receptor and in the various cellular assays using the proceduresdescribed above or found in the scientific literature. Accordingly, theperson of ordinary skill can prepare and evaluate any of the claimedcompounds without undue experimentation.

Any compound found to be effective in modulation of or binding to aKappa opioid receptor can likewise be tested in animal models and inhuman clinical studies using the skill and experience of theinvestigator to guide the selection of dosages and treatment regimens.

It is believed by the inventors herein, and based on informationpublicly available (see cited documents), that modulators of Kappaopioid receptors can be used for treatment of the following medicalconditions:

Affective Disorders: Depression, Stress/Anxiety

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Accordingly, the invention can provide a method of treating a conditionin a human patient for which modulation of a kappa opioid receptor ismedically indicated, comprising administering an effective amount ofconcentration of a compound of the invention at a frequency and for aduration to provide a beneficial effect to the patient, wherein thecondition comprises one or more of an affective disorders comprisingdepression or stress/anxiety; an addictive disorder; alcoholism,epilepsy, a cognition deficiency, schizophrenia, Alzheimer's disease, orpain, e.g., visceral pain or acute post-operative pain.

Bioassay Procedures

The IC50 of each compound shown in Table was with respect to the kappaopioid receptor was determined.

The cell line for the OPRK1 antagonist assay stably expresses thefollowing elements. The carboxy terminus of the OPRK1 receptor has a 7amino acid linker, followed by the TEV protease cleavage site and aGAL4-VP16 fusion protein. The cell line also expresses ab-arrestin-2-TEV protease fusion protein and contains a reporterconstruct consisting of the UAS response element and the b-lactamase(bla) reporter gene. Upon activation of the receptor, g-protein receptorkinase (GRK) phosphorylates specific intracellular residues of OPKR1 andthis induces recruitment of B-arrestin2-TEV protease fusion protein. TheTEV protease recognizes and cleaves the TEV site, releasing theGAL4-VP16 fusion protein, which then translocates to the nucleus. TheGAL4-V16 binds to the UAS element, driving expressing of the b-lactamasegene. B-lactamase expression is detected with the cell permeable,fluorescent substrate, CCF4-AM. This substrate consists of coumarintethered to fluoroscein via a b-lactam ring. In the absence ofb-lactamase, excitation of the dye with 405 nm light results in FRETfrom the coumarin to fluoroscein and emission of green (525 nm maximum)light. B-lactamase cleavage of the substrate separates the courmarinfluorophore from the fluorscein, and 405 nm excitation results in blue(460 nm maximum) emission. The assay is monitored by the blue/greenemission ratio.

The antagonist assay is performed by seeding the cells into 384 wellplates and incubating them 16-24 hours at 37° C. Test antagonistcompounds are added and incubated for 30 minutes at 37° C. Next an EC80challenge of U-50488 (OKRK1 agonist) is added and the samples areincubated for 4 hours at 37° C., followed by addition of CCF4-AMsubstrate. The plates are then incubated 2 hours at room temperature inthe dark and the blue/green ratio determined on a fluorescent platereader. See J Biomol Screen April 2009, vol. 14 no. 4, pp 381-394.

Bioassay Results

For the 118 compounds of table 1, 22 were found to have IC50 values of10-100 nM, 46 had IC50 values of 100-1000 nM, 44 had IC50 values of1000-10,000 nM, and 6 had IC50 values of greater than 10,000 nM

While the invention has been described and exemplified in sufficientdetail for those skilled in this art to make and use it, variousalternatives, modifications, and improvements will be apparent to thoseskilled in the art without departing from the spirit and scope of theclaims.

All patents and publications referred to herein are incorporated byreference herein to the same extent as if each individual publicationwas specifically and individually indicated to be incorporated byreference in its entirety.

The terms and expressions which have been employed are used as terms ofdescription and not of limitation, and there is no intention that in theuse of such terms and expressions of excluding any equivalents of thefeatures shown and described or portions thereof, but it is recognizedthat various modifications are possible within the scope of theinvention claimed. Thus, it should be understood that although thepresent invention has been specifically disclosed by preferredembodiments and optional features, modification and variation of theconcepts herein disclosed may be resorted to by those skilled in theart, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the appended claims.

What is claimed is:
 1. A compound of the following formula:

wherein Y is H, halo, (C₁-C₆)alkyl, or (C₃-C₉)cycloalkyl; Z isheteroaryl; W and X taken together with the atoms to which they arebonded form a fused cycloalkyl or aryl, either of which can be mono- orindependently multi-substituted with (C₁-C₆)alkyl, (C₃-C₉)cycloalkyl,halo, nitro, NR^(a)R^(b), N(R^(a))C(═O)(C₁-C₆)alkyl, CO₂R, orheteroaryl; wherein any alkyl, cycloalkyl, aryl, or heteroaryl of W, X,Y, or Z, can be unsubstituted or can be mono- or independentlymulti-substituted with (C₁-C₆)alkyl, (C₃-C₉)cycloalkyl, halo, nitro,NR^(a)R^(b), N(R^(a))C(═O)(C₁-C₆)alkyl, CO₂R, or heteroaryl; R^(a) andR^(b) are each independently H, alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, or heterocyclylalkyl, wherein any alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl, is substituted with0, 1, 2, 3, or 4 independently selected J, and wherein any heterocyclylor cycloalkyl is mono-, bi-, or tri-cyclic; or R^(a) and R^(b) togetherwith the nitrogen atom to which they are bonded form a heterocyclyl ringsubstituted with 0, 1, 2, 3, or 4 independently selected J; n=0, 1, or2; J is independently at each occurrence OR, (C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₃-C₉)cycloalkyl, CO₂R, or halo; wherein eachindependently selected R is H, (C₁-C₆)alkyl, (C₃-C₉)cycloalkyl,(C₆-C₁₀)aryl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; or any pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1 wherein Y is H. 3.The compound of claim 1 wherein Y is (C₁-C₆)alkyl.
 4. The compound ofclaim 1 wherein Y is halo.
 5. The compound of claim 1 wherein Z is3-methyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl, or3-cyclopropyl-1,2,4-oxadiazol-5-yl.
 6. The compound of claim 1 wherein Wand X taken together with the atoms to which they are bonded form afused aryl which can be mono- or independently multi-substituted with(C₁-C₆)alkyl, (C₃-C₉)cycloalkyl, or halo.
 7. The compound of claim 1wherein n is 0 or 1; R^(a) is ethyl, 2-pentyl, 4-methyl-2-pentyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bornyl, oradamantyl, any of which is substituted with 0, 1, 2, 3, or 4 J; andR^(b) is H.
 8. The compound of claim 1 wherein n is 0 or 1; and R^(a)and R^(b) together with the nitrogen atom to which they are bonded forma pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, or thiomorpholinylring, any of which is substituted with 0, 1, 2, 3, or 4 J.
 9. Thecompound of claim 1 wherein n is
 0. 10. The compound of claim 1 whereinn is 0; R^(a) is heterocyclyl; and R^(b) is H.
 11. The compound of claim10 wherein W and X taken together with the atoms to which they arebonded form a fused aryl which can be mono- or independentlymulti-substituted with (C₁-C₆)alkyl or halo; Y is H or (C₁-C₆)alkyl; andZ is 3-methyl-1,2,4-oxadiazol-5-yl.
 12. The compound of claim 1 whereinthe compound is any of the following:

or any pharmaceutically acceptable salt thereof; wherein rac denotes aracemic mixture, trans-rac denotes a ring trans compound as a racemicmixture, and cis-rac indicates a ring cis compound as a racemic mixture.13. A pharmaceutical composition comprising a compound of any one ofclaims 1-12, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.
 14. The compound of claim 10wherein R^(a) is tetrahydropyranyl.
 15. The compound of claim 14 whereinR^(a) is


16. The compound of claim 10 wherein R^(a) is tetrahydrofuranyl.
 17. Thecompound of claim 16 wherein R^(a) is


18. The compound of claim 10 wherein R^(a) is oxetanyl.
 19. The compoundof claim 18 wherein R^(a) is


20. The compound of claim 9 wherein R^(a) is cycloalkylalkyl and R^(b)is H.
 21. The compound of claim 20 wherein R^(a) is


22. The compound of any one of claims 14-21 wherein Y is H; and W and Xtaken together with the atoms to which they are bonded form the fusedaryl quinoline mono- or independently multi-substituted with(C₁-C₆)alkyl or halo.
 23. The compound of claim 22 wherein Z is3-methyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl or3-cyclopropyl-1,2,4-oxadiazol-5-yl.
 24. The compound of any one ofclaims 14-21 wherein Y is methyl; and W and X taken together with theatoms to which they are bonded form the fused aryl quinoline mono- orindependently multi-substituted with (C₁-C₆)alkyl or halo.
 25. Thecompound of claim wherein 24 is 3-methyl-1,2,4-oxadiazol-5-yl,3-ethyl-1,2,4-oxadiazol-5-yl or 3-cyclopropyl-1,2,4-oxadiazol-5-yl.